ACC is an enzyme that converts acetyl-CoA to malonyl-CoA, and catalyzes a rate-limiting reaction in metabolism or synthesis of fatty acid. Malonyl-CoA, which is produced by an ACC-catalyzed reaction, inhibits fatty acid oxidation in mitochondria based on the feedback inhibition of carnitine palmitoyl transferase-1 (CPT-1). Accordingly, ACC plays a key role in controlling the balance between use of carbohydrate and fatty acid in the liver and skeletal muscle, and controlling insulin sensitivity in the liver, skeletal muscle and adipose tissue.
A reduced level of malonyl-CoA by ACC inhibition can promote increased fatty acid oxidation, suppression of fatty acid synthesis, decreased secretion of triglyceride (TG)-rich lipoprotein (VLDL) in the liver, regulation of insulin secretion in the pancreas, and improvement in the insulin sensitivity in the liver, skeletal muscle and adipose tissue.
In addition, long-term administration of a compound having an ACC inhibitory action can strikingly decrease the TG content of the liver and adipose tissues and selectively decrease body fat in obese test subjects taking low fat diet, by promoting fatty acid oxidation and suppressing de novo synthesis of fatty acid.
Accordingly, a compound having an ACC inhibitory action is extremely useful for the prophylaxis or treatment of metabolic syndrome, obesity, hypertension, diabetes, cardiovascular diseases associated with atherosclerosis, and the like.
On the other hand, WO 2004/096757 A1 (patent document 1) has reported a compound represented by the formula:
whereinR1 is C1-6 alkyl or the like;R3 is Z—X2 wherein Z is CH2 or the like; and X2 is OH or the like;R2 is optionally substituted phenyl (the substituent is an alkoxy group or the like);X is a bond, O or the like;R4 and R5 are each independently H, optionally substituted C1-4 alkyl, acyl or the like; andring a and ring b are each independently aryl, heterocycle or the like,as an agent for the treatment of lymphocyte-mediated diseases or autoimmune diseases.
US 2012/0010247 A1 (patent document 2) has reported a compound represented by the formula:
whereinA is an acyl group or an optionally substituted 5- or 6-membered aromatic ring group;ring M is an optionally fused 5- to 7-membered ring which is optionally further substituted;for ring P and ring Q(1) ring P is an optionally further substituted 5-membered heterocycle, ring Q is an optionally further substituted 6-membered ring, and ring P and ring Q are fused to form an optionally further substituted bicyclic heterocycle, or(2) ring P is an optionally further substituted 5-membered non-aromatic ring, ring Q is an optionally further substituted 6-membered aromatic ring, and ring P and ring Q are fused to form an optionally further substituted bicyclic non-aromatic ring;R1 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-6 cycloalkyl group; andL1 and L2 are(1) independently optionally substituted methylene, O, S, SO or SO2, or(2) L1 and L2 in combination form optionally substituted vinylene, or ethynylene,provided that(a) a compound wherein A is an α-aminoisobutyroyl group; and(b) a compound wherein A is a 5- or 6-membered aromatic ring group substituted bya group represented by the formula: —CO—(CH2)3—COORA1 wherein RA1 is a hydrogen atom or a C1-6 alkyl group, ora group represented by the formula: —CO—NRA2—CRA3RA4—CRA5RA6—COORA7 wherein RA2, RA3, RA4, RA5 and RA7 are each independently a hydrogen atom or a C1-6 alkyl group; and RA6 is a hydrogen atom, a C1-6 alkyl group or a hydroxy group.are excluded,as a compound having an ACC inhibitory action.
US 2011/0263562 A1 (patent document 3) has reported a compound represented by the formula:
whereinR1 is a group represented by the formula: —COR2 wherein R2 is a hydrogen atom or a substituent, an optionally substituted 5- or 6-membered aromatic heterocyclic group or an optionally substituted phenyl group;R3 is a C1-6 alkyl group optionally substituted by halogen atom(s), or an optionally substituted C3-6 cycloalkyl group;R4 is a hydrogen atom or a substituent;X is O, CO, CR5aR5b (wherein R5a and R5b are each independently a hydrogen atom, a halogen atom or an optionally substituted C1-6 alkyl group), NR5c (wherein R5c is a hydrogen atom or an optionally substituted C1-6 alkyl group), S, SO or S(O)2;ring A is an optionally further substituted 4- to 7-membered non-aromatic ring (the ring is optionally bridged);ring P is a 5-membered aromatic heterocycle, ring Q is an optionally further substituted 6-membered ring, and ring P and ring Q are fused to form an optionally further substituted bicyclic aromatic heterocycle; andR6 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-6 cycloalkyl group.as a compound having an ACC inhibitory action.
US 2012/0142714 A1 (patent document 4) has reported a compound represented by the formula:
whereinR1 is a group represented by the formula: —COR2 wherein R2 is a hydrogen atom or a substituent, or an optionally substituted 5- or 6-membered aromatic ring group;R3 is a C1-6 alkyl group optionally substituted by halogen atom(s), or an optionally substituted C3-6 cycloalkyl group;R4a and R4b are each independently a hydrogen atom or a substituent;X is O, CO, CR5aR5b wherein R5a and R5b are each independently a hydrogen atom or a substituent, NR5c wherein R5c is a hydrogen atom or an optionally substituted C1-6 alkyl group, S, SO, or S(O)2;ring A is an optionally further substituted 5- or 6-membered aromatic ring;for ring P and ring Q,(1) ring P is an optionally further substituted 5-membered aromatic ring, ring Q is an optionally further substituted 6-membered ring, and ring P and ring Q are fused to form an optionally further substituted bicyclic aromatic ring, or(2) ring P is an optionally further substituted 5-membered non-aromatic ring, ring Q is an optionally further substituted 6-membered aromatic ring, and ring P and ring Q are fused to form an optionally further substituted bicyclic non-aromatic ring; andR6 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-6 cycloalkyl group,as a compound having an ACC inhibitory action.
WO 2012/108478 A1 (patent document 5) has reported a compound represented by the formula:
whereinR1 is a group represented by the formula: —COR2 wherein R2 is a hydrogen atom or a substituent, or an optionally substituted 5- or 6-membered aromatic ring group;R3 is a C1-6 alkyl group optionally substituted by halogen atom(s), or an optionally substituted C3-6 cycloalkyl group;R4a and R4b are each independently a hydrogen atom or a substituent, orR4a and R4b in combination optionally form a 3-membered ring or a 4-membered ring, each of which is optionally substituted;R5a and R5b are each independently a hydrogen atom or a substituent orR5a and R5b in combination optionally form a 3-membered ring or a 4-membered ring, each of which is optionally substituted;R6 is an optionally substituted C1-6 alkyl group or an optionally substituted C3-6 cycloalkyl group;X is O, CO, CR7aR7b wherein R7a and R7b are each independently a hydrogen atom or a substituent, NR7c wherein R7c is a hydrogen atom or an optionally substituted hydrocarbon group, S, SO, or S(O)2;Y is O, CO, CR8aR8b wherein R8a and R8b are each independently a hydrogen atom or a substituent, NR8c wherein R8c is a hydrogen atom or an optionally substituted hydrocarbon group, S, SO, or S(O)2;ring P is an optionally further substituted 3- to 7-membered ring; andring Q is an optionally further substituted 5- or 6-membered aromatic ring,as a compound having an ACC inhibitory action.
JP 2012-106958 A (patent document 6) has reported a compound represented by the formula:
whereinR1 and R4 are the same or different and each is a hydrogen atom or C1-6 alkyl optionally having substituent(s);R2 is C1-6 alkyl optionally having substituent(s);R3 and R5 are the same or different and each is a cyclic group optionally having substituent(s) or C1-6 alkyl optionally having substituent(s); andring A is a heterocycle optionally having substituent(s), as an IAP antagonist which is a compound useful for the prophylaxis or treatment of cancer and the like.